2-190060319-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005259.3(MSTN):c.490G>A(p.Glu164Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,612,876 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 25 hom. )

Consequence

MSTN
NM_005259.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.22

Publications

19 publications found

Variant links:

Genes affected

MSTN (HGNC:4223): (myostatin) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein negatively regulates skeletal muscle cell proliferation and differentiation. Mutations in this gene are associated with increased skeletal muscle mass in humans and other mammals. [provided by RefSeq, Jul 2016]

MSTN links:

C2orf88 (HGNC:28191): (chromosome 2 open reading frame 88) Predicted to enable protein kinase A regulatory subunit binding activity. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

C2orf88 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031317472).

BP6

Variant 2-190060319-C-T is Benign according to our data. Variant chr2-190060319-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 333238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00143 (217/151986) while in subpopulation EAS AF = 0.0283 (146/5166). AF 95% confidence interval is 0.0245. There are 1 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSTN	NM_005259.3 link	c.490G>A	p.Glu164Lys	missense_variant	Exon 2 of 3	ENST00000260950.5	NP_005250.1	O14793Q53S46
AKAP19	XM_047446008.1 link	c.-517-19635C>T		intron_variant	Intron 2 of 6		XP_047301964.1
AKAP19	XM_047446009.1 link	c.-517-19635C>T		intron_variant	Intron 1 of 5		XP_047301965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSTN	ENST00000260950.5 link	c.490G>A	p.Glu164Lys	missense_variant	Exon 2 of 3	1	NM_005259.3	ENSP00000260950.3	O14793
C2orf88	ENST00000478197.1 link	n.220-18904C>T		intron_variant	Intron 1 of 1	4
C2orf88	ENST00000495546.1 link	n.202-19635C>T		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000629

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00204

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0280

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00326

AC:

817

AN:

250792

AF XY:

0.00281

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0281

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00119

AC:

1738

AN:

1460890

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

823

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.000419

AC:

AN:

33440

American (AMR)

AF:

0.00540

AC:

241

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.0264

AC:

1048

AN:

39674

South Asian (SAS)

AF:

0.00208

AC:

179

AN:

86228

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111300

Other (OTH)

AF:

0.00363

AC:

219

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

106

211

317

422

528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00143

AC:

217

AN:

151986

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

121

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

41488

American (AMR)

AF:

0.00197

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.0283

AC:

146

AN:

5166

South Asian (SAS)

AF:

0.00166

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67926

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.00187

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00302

AC:

367

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Myostatin-related muscle hypertrophy

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.32

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

1.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.5

REVEL

Benign

0.075

Sift

Benign

0.47

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.13

MVP

0.46

MPC

0.27

ClinPred

0.0052

GERP RS

1.6

Varity_R

0.11

gMVP

0.22

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-190060319-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over